{"id":44044,"date":"2014-02-16T20:27:02","date_gmt":"2014-02-17T01:27:02","guid":{"rendered":"http:\/\/1boringoldman.com\/?p=44044"},"modified":"2014-02-20T07:46:30","modified_gmt":"2014-02-20T12:46:30","slug":"sign-it-now","status":"publish","type":"post","link":"https:\/\/1boringoldman.com\/index.php\/2014\/02\/16\/sign-it-now\/","title":{"rendered":"sign it now!…"},"content":{"rendered":"\n

BE WARNED! This post is very<\/u> boring. It’s what an old man does to escape watching any more Olympic figure skating… <\/font><\/em> <\/p>\n

Three years ago, I had my first shot at looking at the FDA Approval documents for a psychiatric drug [seroquel II [version 2.0]: guessing…<\/a>]. To be honest, I didn’t know anything about how to do such a thing, but I had a lot of help. I learned that the FDA approval process requires two decent clinical trials with statistical efficacy and an acceptable side effect profile for approval. I discovered that PubMed<\/a> had the abstracts of the published trials, that clinical trials.gov<\/a> had the trial registrations [and rarely the required posted results], and that in many cases the medical report on the approval were on Drugs@FDA<\/a>. And I learned that this wasn’t an easy avocation. There were lots of things to consider, too many for a rookie like me, and I often ended up with my eyes crossed scratching my head. Later I learned that the FDA is a pretty nice bunch, and if you can’t find what you’re looking for posted online, they’ll send it to you with a simple Freedom of Information Act request<\/a> made online – charging a nominal fee only if you’re a frequent flyer or your request is hard to gather.<\/p>\n

I looked at the FDA original approval of Lurasidone [Latuda®] for Schizophrenia back in 2011 [see ought to know by now…<\/em><\/a>, echo<\/font> echo echo<\/font> echo<\/font> echo<\/font> echo<\/font> echo…<\/font><\/a> , in the shadows…<\/a>, wait…<\/a>] but I didn’t pursue it very far. Frankly, I thought it would be something of a dud with its low efficacy and the generic competition. That wasn’t correct apparently, so I’m taking another look. But that’s not what this post is really about. It’s about why the<\/font><\/strong> AllTrials<\/font><\/a> campaign is absolutely essential<\/font><\/strong>.<\/p>\n

About the Table<\/font><\/strong>: The top five studies were the ones looked at by the FDA. The bottom two were in the works<\/em> but not completed. Study D1050049 was a failed study [inert comparator] so they only considered four [D1050006, D1050196, D1050229, D1050229]. The left-hand column has the study [linked to clinicaltrials.gov], the date started, the number of subjects, the dropout rate, the number of sites, and an icon linking to the abstract if published. The second column has the scale used [BPRSd<\/a> or PANSS<\/a>] and the correction method for missing values [LOCF<\/a> or MMRM<\/a>] with the Primary Variable in bold. The numbers are the raw differences between the drug and placebo. Significant values are bold red: <\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n <\/tr>\n\n\n
LS Mean Difference from Placebo<\/font><\/strong><\/td>\n<\/tr>\n
Study #<\/font><\/strong><\/td>\nEfficacy Scale<\/font><\/strong> <\/td>\n20mg<\/font><\/strong><\/td>\n40mg<\/font><\/strong><\/td>\n80mg<\/font><\/strong><\/td>\n120mg<\/font><\/strong><\/td>\n160mg<\/font><\/strong><\/td>\nComparator<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1050006  US<\/font><\/strong><\/sup>
   2001   n=149<\/sup>
   66% drop out <\/sup>
   15 sites<\/sup> <\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n <\/td>\n-5.6<\/font><\/strong><\/td>\n <\/td>\n-6.7<\/font><\/strong><\/td>\n <\/td>\n <\/td>\n<\/tr>\n
BPRSd (MMRM)<\/td>\n-7.3<\/font><\/strong><\/td>\n-9.2<\/font><\/strong><\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-9.6<\/td>\n-11.0<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
 <\/td>\nHaldol<\/font><\/strong><\/td>\n<\/tr>\n
D1050049<\/font><\/strong><\/a>  US<\/font><\/strong><\/sup>
   2003   n=356<\/sup>
   43% drop out <\/sup>
   34 sites<\/sup><\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n-5.0<\/td>\n-5.2<\/td>\n-8.0<\/td>\n-9.8<\/td>\n <\/td>\n-7.9<\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-7.1<\/td>\n-7.2<\/td>\n-13.6<\/td>\n-16.0<\/td>\n-12.3<\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
<\/a>D1050196<\/font><\/strong><\/a> US<\/font><\/strong><\/sup>
   2004   n=180<\/sup>
   45% drop out <\/sup>
   15 sites<\/sup><\/td>\n		BPRSd (LOCF)<\/font><\/strong><\/td>\n <\/td>\n <\/td>\n-4.7<\/font><\/strong><\/td>\n <\/td>\n <\/td>\n <\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-8.6<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
<\/a>D1050229<\/font><\/strong><\/a> MIX<\/font><\/strong><\/sup>
   2008   n=496<\/sup>
   34% drop out <\/sup>
   48 sites<\/sup><\/td>\n		PANSS (MMRM<\/font><\/strong>)<\/td>\n <\/td>\n-2.1<\/td>\n-6.4<\/font><\/strong><\/td>\n-3.5<\/td>\n <\/td>\n <\/td>\n<\/tr>\n
US Sites<\/td>\n+0.6<\/td>\n-2.0<\/td>\n+0.2<\/td>\n<\/tr>\n
Non-US Sites<\/td>\n-6.5<\/td>\n-10.8<\/font><\/strong><\/td>\n-8.6<\/font><\/strong><\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-2.7<\/font><\/strong><\/td>\n-6.1<\/font><\/strong><\/td>\n-3.5<\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
 <\/td>\nZyprexa<\/font><\/strong><\/td>\n<\/tr>\n
<\/a>D1050231<\/font><\/strong><\/a> MIX<\/font><\/strong><\/sup>
   2009   n=475<\/sup>
   38% drop out <\/sup>
   52 sites<\/sup><\/td>\n		PANSS (MMRM)<\/font><\/strong><\/td>\n <\/td>\n-9.7<\/font><\/strong><\/td>\n <\/td>\n-7.5<\/font><\/strong><\/td>\n <\/td>\n-12.6<\/font><\/strong><\/td>\n<\/tr>\n
US Sites<\/td>\n-5.7<\/td>\n-4.8<\/td>\n-11.4<\/td>\n<\/tr>\n
Non-US Sites<\/td>\n -10.5<\/font><\/strong> <\/td>\n-3.8<\/td>\n-9.6<\/font><\/strong><\/td>\n<\/tr>\n
PANSS (LOCF)<\/td>\n-7.9<\/font><\/strong><\/td>\n-4.8<\/td>\n-11.4<\/font><\/strong><\/td>\n<\/tr>\n
\n
\n
<\/td>\n<\/tr>\n
 <\/td>\nSeroquel<\/font><\/strong><\/td>\n<\/tr>\n
<\/a>D1050233<\/font><\/strong><\/a> MIX<\/font><\/strong><\/sup>
   2008   n=488<\/sup>
   28% drop out <\/sup>
   65 sites<\/sup><\/td>\n		PANSS (MMRM)<\/font><\/strong><\/td>\n <\/td>\n <\/td>\n-11.9<\/font><\/strong> <\/td>\n <\/td>\n-16.2<\/font><\/strong><\/td>\n-17.5<\/font><\/strong><\/td>\n<\/tr>\n
\n
<\/td>\n<\/tr>\n
D1001002<\/font><\/strong><\/a> Asia<\/font><\/strong><\/sup>
   2008   n~440<\/sup>
   62 sites<\/sup><\/td>\n		PANSS<\/font><\/strong> (?)<\/td>\nunpublished<\/font><\/strong><\/td>\n<\/tr>\n<\/table>\n

In addition to the Clinical Trial and PubMed links, I had the FDA Medical Review<\/a> [the source for the values for the unpublished trials], a special report from the FDA Director<\/a>, and the full journal articles for the published studies. Lots of stuff.<\/p>\n

What happened at the FDA<\/font><\/strong>: The medical review was done by Dr. Cara L. Alfaro and was impressive. She concluded:<\/div>\n

… the data submitted in this NDA, in this reviewer’s opinion, do not support the efficacy of lurasidone in the treatment of schizophrenia… <\/p>\n

1.2 Risk Benefit Assessment<\/font><\/strong>: Efficacy has not been established in this NDA submission. The safety profile is more similar to typical antipsychotics with significant akathisia, hyperprolactinemia, parkinsonian-adverse events and dystonias; many of which are dose-related. Lurasidone does not appear to have significant adverse impact on metabolic indices (glucose, lipids, weight, etc.). Lurasidone may be associated with potentially significant hypersensitivity reactions. A comprehensive risk:benefit assessment is premature at this time.<\/div>\n<\/blockquote>\n
She found a lot to be concerned about. There was heavy use of concomitant Benzodiazepines [~60%] and some use other antipsychotics. She didn’t accept trial D1050006 because of its small size and drop-out rate [66%], and didn’t like D1050229 or D1050231 because of inconsistent results and failure at the US sites. The Director of the NIMH Division of Psychiatry Products, Thomas Laughren, conducted his own analysis and recommended approval – which is what the NIMH committee decided to do. I agreed with Dr. Alfaro.<\/div>\n

I was also able to look at one of the studies that wasn’t quite ready for prime time [D1050233]. Even though those numbers may look good, there were some big question marks. There were 65 sites, 36 Non-US, but there was no breakdown between US\/Non-US responses in the article. Even more troubling to me, there were four groups [Placebo, 80mg, 160mg. and Seroquel], 65 sites, and a total of  72% of 488 subjects who completed the study. That means that the average size for each group at any given site was (488 x 0.72) ÷ (65 x 4) = 1.4 subjects\/group\/site. I never heard of such a thing! There’s a way to test for that statistically [General Linear Model with effects for country, site, and treatment]. In English what I’m saying is that it’s almost as possible that the variance is due to site differences as to treatment effect.  They did an "ANCOVA at Week 6 LOCF endpoint with treatment and pooled center as fixed factors and Baseline value as a covariate<\/em>" which doesn’t say country or site to me. But, and this is the point, I don’t have the numbers so I can’t run that down. There’s also enough other strategic language in that article to make me plenty suspicious of the whole presentation. Study D1001002 had no results on clinicaltrial.gov and no publication so I assume it was a bust. <\/p>\n

With all this information that I’ve been able to ferret out, I’m pretty sure that this is one of those situations where the data has been skewed and I doubt that Lurasidone is much of a contender as a drug for Schizophrenia. But I can’t really tell because we can’t have the data to definitively vet these studies. And now we have this month’s indication creep articles [or both…<\/a>, creepy…<\/a>] to think about, with even less to go on. It’s just really frustrating to read these three totally industry generated and industry authored articles in the American Journal of Psychiatry<\/font><\/strong> knowing how distorted the reporting has been with all of the Atypical Antipsychotics and not be able to independently corroborate their conclusions, no matter how many rocks we look under.<\/p>\n

So that’s why the<\/font><\/strong> AllTrials<\/font><\/a> campaign is absolutely essential! If you haven’t signed <\/font><\/strong>the petition<\/a>, sign it now!<\/font><\/strong><\/div>\n
\n
UPDATE<\/font><\/strong>: Effect Sizes with 95% CI calculated from the FDA Medical Review<\/a>:<\/div>\n
 <\/div>\n","protected":false},"excerpt":{"rendered":"

BE WARNED! This post is very boring. It’s what an old man does to escape watching any more Olympic figure skating… Three years ago, I had my first shot at looking at the FDA Approval documents for a psychiatric drug [seroquel II [version 2.0]: guessing…]. To be honest, I didn’t know anything about how to […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_bbp_topic_count":0,"_bbp_reply_count":0,"_bbp_total_topic_count":0,"_bbp_total_reply_count":0,"_bbp_voice_count":0,"_bbp_anonymous_reply_count":0,"_bbp_forum_subforum_count":0,"footnotes":""},"categories":[2],"tags":[],"class_list":["post-44044","post","type-post","status-publish","format-standard","hentry","category-politics"],"_links":{"self":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/44044","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/comments?post=44044"}],"version-history":[{"count":73,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/44044\/revisions"}],"predecessor-version":[{"id":44169,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/posts\/44044\/revisions\/44169"}],"wp:attachment":[{"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/media?parent=44044"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/categories?post=44044"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/1boringoldman.com\/index.php\/wp-json\/wp\/v2\/tags?post=44044"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}